A Drug Abuse Research Center (DARC) is proposed to be established at the Institute for Behavioral Genetics (IBG), University of Colorado, Boulder. Faculty members of IBG are nationally and internationally known for their research in quantitative genetics of human behavioral characters (including cognition, reading disability, personality development, and responses to alcohol) and in behavioral pharmacogenetics. Thus, establishment of a DARC at IBG would facilitate a multidisciplinary approach to the problem of vulnerability to drug abuse. The Research Components proposed include (1) quantitative genetic analyses of the cigarette withdrawal syndrome; (2) a study of the families of severe substance-abusing teenagers; 3) assessment of the tension-reduction hypothesis of nicotine's action and development of animal models of cigarette withdrawal; (4) studies of the effects of amphetamine, cocaine, ethanol, and morphine on neurotensin and dopamine levels in mesolimbic and mesocortical dopaminergic pathways in 8 strains of mice; (5) application of genetic strategies to delineate predispositional factors for cocaine hepatotoxicity, and studies of their potential application to cocaine use and toxicity in humans: (6) studies of the development of tolerance and physical dependence to cocaine and amphetamine in lines of mice selected for high or low open-field activity, and the effects of these drugs on learning and memory in these lines; (7) bi-directional selective breeding to produce replicate lines of mice which differ in responses to nicotine, and to cocaine; and (8) determination of the relationship between cocaine initial sensitivity, tolerance or sensitization acquisition, and withdrawal severity in inbred strains of mice. The investigators will benefit by sharing scientific resources such as the specific-pathogen-free mouse facility and twin/adoptee registers, and from comparing results derived from a common database of inbred strains and selected lines of mice to those derived from human subjects. Results obtained from research conducted within the proposed DARC should contribute to a better understanding of the etiology of individual differences in drug- related behaviors, and should add a valuable knowledge base for clinical intervention strategies for the individual.